Background Several somatic mutation hotspots were recently identified in the TERT promoter region in human cancers. Large scale studies of these mutations in multiple tumor types are limited, in particular in Asian populations. This study aimed to: analyze TERT promoter mutations in multiple tumor types in a large Chinese patient cohort, investigate novel tumor types and assess the functional significance of the mutations. Methods TERT promoter mutation status was assessed by Sanger sequencing for 13 different tumor types and 799 tumor tissues from Chinese cancer patients. Thymic epithelial tumors, gastrointestinal leiomyoma, and gastric schwannoma were included, for which the TERT promoter has not been previously sequenced. Functional studies included TERT expression by RT-qPCR, telomerase activity by the TRAP assay, and promoter activity by the luciferase reporter assay. Results TERT promoter mutations were highly frequent in glioblastoma (83.9%), urothelial carcinoma (64.5%), oligodendroglioma (70.0%), medulloblastoma (33.3%), and hepatocellular carcinoma (31.4%). C228T and C250T were the most common mutations. In urothelial carcinoma, several novel rare mutations were identified. TERT promoter mutations were absent in GIST, thymic epithelial tumors, gastrointestinal leiomyoma, gastric schwannoma, cholangiocarcinoma, gastric and pancreatic cancer. TERT promoter mutations highly correlated with upregulated TERT mRNA expression and telomerase activity in adult gliomas. These mutations differentially enhanced the transcriptional activity of the TERT core promoter. Conclusions TERT promoter mutations are frequent in multiple tumor types and have similar distributions in Chinese cancer patients. The functional significance of these mutations reflect the importance to telomere maintenance and hence tumorigenesis, making them potential therapeutic targets.

Chronic infection of Mycoplasma hyorhinis (M. hyorhinis) has been postulated to be associated with several types of cancer, but its effect on patients' survival and host factors mediating its infection remain unclear. Herein, we demonstrated that M. hyorhinis p37 protein expression in gastric cancer tissues predicts poor survival and associates with metastasis. M. hyorhinis infects mammalian cells and promotes gastric cancer cell invasiveness via its membrane protein p37. Synthesized peptide corresponding to the N-terminus of p37 prevents M. hyorhinis infection. Host Annexin A2 (ANXA2) interacts with the N-terminus of p37. In addition, EGFR forms a complex with p37 and ANXA2, and is required for M. hyorhinis-induced phosphorylation and membrane recruitment of ANXA2. M. hyorhinis infection is inhibited by siRNA-mediated knockdown of ANXA2 or EGFR, but is enhanced by expression of ectopic ANXA2 or EGFR. Downstream of ANXA2 and EGFR, the NF-kB pathway is activated and mediates M. hyorhinis-driven cell migration. In conclusion, our study unveils the effect of M. hyorhinis infection on gastric cancer survival and uncovers the mechanisms by which M. hyorhinis infects mammalian cells and promotes cancer cell migration. Cancer Res; 74(20); 5782-94. Ó2014 AACR.

Mucinous tubular and spindle cell renal cell carcinoma is a rare, recently described variant of renal cell carcinoma characterized by an admixture of cuboidal cells in tubules and sheets of spindle cells, and variable amounts of mucinous stroma. It has been recognized as a distinct entity in the 2004 World Health Organization tumor classification. Since then, several dozen of these tumor have been reported with additional complementary morphologic characteristics, immunohistochemical profile, and molecular genetic features that have further clarified its clinicopathologic aspects. Although originally considered as a low grade renal cell carcinoma on the basis of its bland appearing nuclear features and indolent clinical course, mucinous tubular and spindle cell renal cell carcinoma has currently been proven to be a tumor that has a histological spectrum ranging from low to high grade that includes sarcomatoid differentiation. In this review, we present a detailed summary of the current knowledge regarding the clinicopathologic, immunohistochemical, molecular genetic, and prognostic characteristics, as well as differential diagnoses of mucinous tubular and spindle cell renal cell carcinoma.

Background Inspired by nature, the biomimetic approach has been incorporated into drug nanocarriers for cancer targeted chemotherapy. The nanocarriers are cloaked in cell membranes, which enables them to incorporate the functions of natural cells. Key scientific concepts of review Nanocarriers surface engineered with cell membranes have emerged as a fascinating source of materials for cancer targeted chemotherapy. A distinctive characteristic of cell membrane-coated nanocarriers (CMCNs) is that they include carbohydrates, proteins, and lipids, in addition to being biocompatible. CMCNs are capable of interacting with the complicated biological milieu of the tumor because they contain the signaling networks and intrinsic functions of their parent cells. Numerous cell membranes have been investigated for the purpose of masking nanocarriers with membranes, and various tumor-targeting methods have been devised to improve cancer targeted chemotherapy. Moreover, the diverse structure of the membrane from different cell sources broadens the spectrum of CMCNs and offers an entirely new class of drug-delivery systems. Aim of review This review will describe the manufacturing processes for CMCNs and the therapeutic uses for different kinds of cell membrane-coated nanocarrier-based drug delivery systems, as well as addressing obstacles and future prospects. Graphical Abstract

High-mobility group box 1 (HMGB1) functions as a proinflammatory cytokine and is one of the most intriguing molecules in inflammatory disorders and cancers. Notably, HMGB1 is a potential therapeutic target and novel biomarker in related diseases. However, the diagnostic value of HMGB1 for benign and malignant asbestos-related diseases (ARDs) remains unclear. In this work, we detected preoperative serum HMGB1 levels in Chinese asbestos-exposed (AE) and ARDs populations and further evaluated the diagnostic value of HMGB1 in patients with certain types of ARDs, including those with pleural plaques, asbestosis, or malignant mesothelioma (MM). The experimental data presented that the serum level of HMGB1 was significantly elevated in AE and ARDs subjects. Our findings indicated that serum HMGB1 is a sensitive and specific biomarker for discriminating asbestosis- and MM-affected individuals from healthy or AE individuals. In addition, serum matrix metalloproteinases 2 and 9 are not correlated with HMGB1 in ARDs. Thus, our study provides supporting evidence for HMGB1 as a potential biomarker either for the clinical diagnosis of high-risk AE cohorts or for evaluating ARDs.

the role of forkhead box O3 (FOXO3) as a tumor suppressor gene and its association with the human lifespan is well documented. However, several studies have indicated that high expression of FOXO3 is also significantly associated with tumorigenesis. the aim of the present study was to determine the clinical significance of FOXO3 in the development and prognosis of hepatocellular carcinoma (Hcc). mrnA expression data of FOXO3 from the cancer genome Atlas database was analyzed through the UAlcAn online tool to compare the expression of FOXO3 between Hcc and normal liver tissues. subsequently, the expression of FOXO3 at the protein level was investigated via immunohistochemical staining of 314 Hcc and 150 non-cancerous liver tissue samples. the association between protein expression and clinicopathological parameters was analyzed using the χ 2 test, and the effect of FOXO3 expression on survival was assessed via Kaplan-Meier analysis. the expression of FOXO3 mRNA was significantly higher in HCC in comparison with healthy tissues. High FOXO3 protein expression was revealed in 43/150 non-cancerous liver tissues, and in 238/314 Hcc samples. A significant association was demonstrated between FOXO3 expression and metastasis, tumor-node-Metastasis stage, edmondson grade, α-fetoprotein level and overall survival. In conclusion, the high expression of FOXO3 predicts a poor prognosis in patients with Hcc, indicating this protein as a potential therapeutic target in Hcc.

This study aims to investigate the prognostic power of carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6) in gastric cancer (GC) and its potential role in cancer development and progression. Data mining results show that CEACAM6 is overexpressed in gastric cancer and is correlated with lymph node metastasis. Subsequently, immunohistochemical staining was performed to determine CEACAM6 protein levels in paraffin gastric tumor specimens. Real-time reverse-transcription-polymerase chain reaction (RT-PCR) was conducted to detect CEACAM6 mRNA levels in fresh GC samples. CEACAM6 protein and mRNA levels were significantly up regulated in GC compared with paired normal mucosa. The IHC staining intensity of CEACAM6 was positively correlated with tumor size, Lauren's classification, vascular invasion, lymph node metastasis, distant metastasis, and TNM stage. CEACAM6 expression was inversely correlated with the five-year survival rate of GC patients. Cox multivariate analysis results demonstrated that the overall survival was independently correlated with CEACAM6 expression. A significant association was observed between CEACAM6 and distant metastases. Network analysis of downstream gene signatures revealed several hub genes such as SRC and DNM1L etc. which may mediating tumor promoting functions of CEACAM6. Further data mining discovered that Tamoxifen etc. could be therapeutic alternatives for gastric patients with CEACAM6 overexpression. Collectively, CEACAM6 overexpression is a common characteristic of GC and is associated with poor 5 year survival rate in GC. Besides, potential molecular mechanisms and treatment options were also provided.

Fibulin-3 has been reported as a potential biomarker for mesothelioma. However, little is known about the diagnostic efficacies of fibulin-3 for asbestos-related diseases (ARDs) in China. This study was to investigate the utility of fibulin-3 for asbestos exposure and ARDs. A total of 430 subjects were recruited from Southeast China, including healthy individuals, asbestos-exposed (AE) individuals, and patients with pleural plaques (PP), asbestosis, and malignant pleural mesothelioma (MPM). Plasma fibulin-3 was measured using the enzyme-linked immunosorbent assay. Linear regression analyses were applied to explore the influencing factors of fibulin-3. Receiver operating characteristic curves were used to determine the cutoff values. The median fibulin-3 level of subjects in the mesothelioma group was higher than that in other groups. Subjects in the asbestosis group had higher median fibulin-3 level than those in the control group. A higher fibulin-3 level was found in the group with ≥10 years of asbestos exposure as compared with control groups. The AUCs of fibulin-3 for distinguishing MPM subjects from control, AE, PP, and asbestosis subjects were 0.92, 0.88, 0.90, and 0.81, respectively. Our study provided evidence that fibulin-3 could be a potential biomarker for the early screening of MPM, but not of other nonmalignant ARDs in Chinese populations.